angiotensinogen and Chronic-Disease

The increased activity of intrarenal renin-angiotensin system (RAS) in a setting of elevated arterial pressure elicits renal vasoconstriction, increased sodium reabsorption, proliferation, fibrosis and renal injury. Increases in intrarenal and interstitial angiotensin (Ang) II levels are due to increased AT(1) receptor mediated Ang II uptake and stimulation of renal angiotensinogen (AGT) mRNA and protein expression. Augmented proximal tubule AGT production increases tubular AGT secretion and spillover of AGT into the distal nephron and urine. Increased renin formation by principal cells of the collecting ducts forms Ang I from AGT thus increasing Ang II. The catalytic actions of renin and prorenin are enhanced by prorenin receptors (PRRs) on the intercalated cells. The resultant increased intrarenal Ang II levels contribute to the genesis of chronic hypertension.

Topics: Angiotensin II; Angiotensinogen; Animals; Chronic Disease; Humans; Hypertension; Kidney; Kidney Tubules, Collecting; Prorenin Receptor; Receptors, Cell Surface; Renin

In recent years, the focus of interest on the role of the renin-angiotensin system (RAS) in the pathophysiology of hypertension and organ injury has changed to a major emphasis on the role of the local RAS in specific tissues. In the kidney, all of the RAS components are present and intrarenal angiotensin II (Ang II) is formed by independent multiple mechanisms. Proximal tubular angiotensinogen, collecting duct renin, and tubular angiotensin II type 1 (AT1) receptors are positively augmented by intrarenal Ang II. In addition to the classic RAS pathways, prorenin receptors and chymase are also involved in local Ang II formation in the kidney. Moreover, circulating Ang II is actively internalized into proximal tubular cells by AT1 receptor-dependent mechanisms. Consequently, Ang II is compartmentalized in the renal interstitial fluid and the proximal tubular compartments with much higher concentrations than those existing in the circulation. Recent evidence has also revealed that inappropriate activation of the intrarenal RAS is an important contributor to the pathogenesis of hypertension and renal injury. Thus, it is necessary to understand the mechanisms responsible for independent regulation of the intrarenal RAS. In this review, we will briefly summarize our current understanding of independent regulation of the intrarenal RAS and discuss how inappropriate activation of this system contributes to the development and maintenance of hypertension and renal injury. We will also discuss the impact of antihypertensive agents in preventing the progressive increases in the intrarenal RAS during the development of hypertension and renal injury.

Topics: Angiotensin II; Angiotensinogen; Animals; Antihypertensive Agents; Chronic Disease; Disease Models, Animal; Humans; Hypertension; Hypertension, Renal; Kidney; Kidney Diseases; Receptors, Angiotensin; Renin; Renin-Angiotensin System

In the the vast majority of patients undergoing kidney transplantation, long-term success is markedly limited by a gradual decrease in graft function over time, often termed as "chronic rejection" or "chronic allograft injury." Although there have been no formal studies examining the role of genetic factors other than those related to histocompatibility for the development or progression of chronic allograft rejection, it is likely that genetic factors affecting blood pressure regulation, mesangial or vascular proliferation, or aspects of inflammatory response including thrombosis, chemotaxis, or fibrosis may play an important role in this complex syndrome. There is currently little hope that the responsible genes can be identified through sib-pair or linkage studies in families. Therefore, the study of candidate genes selected on the basis of our current understanding of the pathophysiological mechanisms involved in the chronic rejection response appears the only feasible approach. Thus far, studies have focused mainly on the role of functional genetic variants of the renin-angiotensin system on renal allograft funding. These studies, however, have not identified these variants as important determinants of renal allograft survival. Clearly, future studies will have to address the role of other variants of this system as well as genes encoding for other systems deemed to be of pathophysiological significance for the development and progression of chronic transplant injury.

Topics: Angiotensinogen; Animals; Chronic Disease; Genetic Variation; Graft Rejection; Humans; Kidney Transplantation; Peptidyl-Dipeptidase A; Renin-Angiotensin System

The current study tested the hypothesis that urinary angiotensinogen (UAGT) and urinary monocyte chemoattractant protein-1 (UMCP-1) levels provide a specific index of intrarenal renin-angiotensin system (RAS) status and the degree of infiltration of macrophages associated with RAS blockade and immunosuppressant treatment in pediatric patients with chronic glomerulonephritis.. We measured baseline UAGT and UMCP-1 levels to examine the correlation between glomerular injury in 48 pediatric chronic glomerulonephritis patients before treatment. Furthermore, we performed immunohistochemical analysis of angiotensinogen (AGT) and CD68 in 27 pediatric chronic glomerulonephritis patients treated with RAS blockades and immunosuppressants for 2 years. Finally, we examined the effects of angiotensin II (Ang II) on monocyte chemoattractant protein-1 (MCP-1) expression in cultured human mesangial cells (MCs).. Baseline UAGT and UMCP-1 levels positively correlated with urinary protein levels, scores for mesangial hypercellularity, rate of crescentic formation, and expression levels of AGT and CD68 in renal tissues (p < 0.05). UAGT and UMCP-1 levels were significantly decreased after RAS blockade and immunosuppressant treatment (p < 0.01), which was accompanied by AGT and CD68 (p < 0.01), as well as the magnitude of glomerular injury. Cultured human MCs showed increased MCP-1 messenger ribonucleic acid and protein levels after Ang II treatment (p < 0.01).. The data indicates that UAGT and UMCP-1 are useful biomarkers of the degree of glomerular injury during RAS blockade and immunosuppressant treatment in pediatric patients with chronic glomerulonephritis.

Topics: Angiotensin II; Angiotensinogen; Chemokine CCL2; Child; Chronic Disease; Glomerulonephritis; Humans; Immunosuppressive Agents; Kidney; Macrophages; Renin-Angiotensin System

We investigated oxidative stress and RAAS biomarkers, as well as their association, in chronic heart failure (CHF) patients on optimized medical therapy, stratified by disease severity or by renal function. Since vitamin D has been shown to attenuate RAAS activation and oxidative stress, we further evaluated the relationship between vitamin D, RAAS and oxidative stress in CHF patients with or without renal impairment. Sixty CHF outpatients were included and stratified by disease severity or by renal function. We quantified urinary hydrogen peroxide, plasma and urinary isoprostanes, plasma total antioxidant status, urinary angiotensinogen (intrarenal RAAS activation biomarker) and plasma angiotensinogen, plasma renin and aldosterone concentration, serum angiotensin-converting enzyme (ACE) activity, plasma angiotensin peptides, and serum total 25-hydroxyvitamin D (S-total 25(OH)D). Severe CHF patients had higher urinary isoprostanes (p = 0.002) and lower S-total 25(OH)D (p = 0.006) compared to mild-to-moderate patients, but no differences were observed for other redox or RAAS biomarkers. Patients with impaired renal function (iRF) had higher urinary angiotensinogen (p = 0.003) and lower S-total 25(OH)D (p = 0.028) compared to those with normal renal function (nRF), while no differences were observed for the remaining RAAS and redox parameters. Several positive correlations between oxidative stress and RAAS biomarkers were detected in iRF patients, while in patients with nRF these correlations were primarily inverse. In CHF-iRF patients, S-25(OD)D was inversely associated with urinary isoprostanes, which in turn were positively associated with plasma angiotensinogen and serum ACE. In conclusion, CHF patients with renal function impairment have increased intrarenal RAAS activation and lower vitamin D values and might benefit from the combination of RAAS blockers with vitamin D and/or antioxidants.

Topics: Aged; Angiotensinogen; Biomarkers; Chronic Disease; Female; Glomerular Filtration Rate; Heart Failure; Humans; Isoprostanes; Kidney; Kidney Diseases; Male; Middle Aged; Oxidative Stress; Peptidyl-Dipeptidase A; Renin-Angiotensin System; Severity of Illness Index; Vitamin D

Heart failure with preserved ejection fraction (HFpEF) can arise from cardiac and vascular remodeling processes following long-lasting hypertension. Efficacy of common HF therapeutics is unsatisfactory in HFpEF. Evidence suggests that stimulators of the nitric oxide-sensitive soluble guanylyl cyclase (NOsGC) could be of use here. We aimed to characterize the complex cardiovascular effects of NOsGC stimulation using NO-independent stimulator BAY 41-8543 in a double-transgenic rat (dTGR) model of HFpEF. We show a drastically improved survival rate of treated dTGR. We observed less cardiac fibrosis, macrophage infiltration, and gap junction remodeling in treated dTGR. Microarray analysis revealed that treatment of dTGR corrected the dysregulateion of cardiac genes associated with fibrosis, inflammation, apoptosis, oxidative stress, and ion channel function toward an expression profile similar to healthy controls. Treatment reduced systemic blood pressure levels and improved endothelium-dependent vasorelaxation of resistance vessels. Further comprehensive in vivo phenotyping showed an improved diastolic cardiac function, improved hemodynamics, and less susceptibility to ventricular arrhythmias. Short-term BAY 41-8543 application in isolated untreated transgenic hearts with structural remodeling significantly reduced the occurrence of ventricular arrhythmias, suggesting a direct nongenomic role of NOsGC stimulation on excitation. Thus, NOsGC stimulation was highly effective in improving several HFpEF facets in this animal model, underscoring its potential value for patients.

Topics: Administration, Oral; Angiotensinogen; Animals; Arrhythmias, Cardiac; Blood Pressure; Chronic Disease; Disease Models, Animal; Drug Evaluation, Preclinical; Echocardiography; Heart Failure; Heart Ventricles; Humans; Isolated Heart Preparation; Male; Morpholines; Pyrimidines; Rats; Rats, Transgenic; Renin; Soluble Guanylyl Cyclase; Stroke Volume; Survival Rate; Treatment Outcome

Black ethnicity is associated with worse pregnancy outcomes in women with chronic hypertension. Preexisting endothelial and renal dysfunction and poor placentation may contribute, but pathophysiological mechanisms underpinning increased risk are poorly understood. This cohort study aimed to investigate the relationship between ethnicity, superimposed preeclampsia, and longitudinal changes in markers of endothelial, renal, and placental dysfunction in women with chronic hypertension. Plasma concentrations of placental growth factor (PlGF), syndecan-1, renin, and aldosterone and urinary angiotensinogen-to-creatinine ratio (AGTCR), protein-to-creatinine ratio (PCR), and albumin-to-creatinine ratio (ACR) were quantified during pregnancy and postpartum in women with chronic hypertension. Comparisons of longitudinal biomarker concentrations were made using log-transformation and random effects logistic regression allowing for gestation. Of 117 women, superimposed preeclampsia was diagnosed in 21% ( n = 25), with 24% ( n = 6) having an additional diagnosis of diabetes. The cohort included 63 (54%) women who self-identified as being of black ethnicity. PlGF concentrations were 67% lower [95% confidence interval (CI) -79 to -48%] and AGTCR, PCR, and ACR were higher over gestation, in women with subsequent superimposed preeclampsia (compared with those without superimposed preeclampsia). PlGF <100 pg/ml at 20-23.9 wk of gestation predicted subsequent birth weight <3rd percentile with 88% sensitivity (95% CI 47-100%) and 83% specificity (95% CI 70-92%). Black women had 43% lower renin (95% CI -58 to -23%) and 41% lower aldosterone (95%CI -45 to -15%) concentrations over gestation. Changes in placental (PlGF) and renal (AGTCR/PCR/ACR) biomarkers predated adverse pregnancy outcome. Ethnic variation in the renin-angiotensin-aldosterone system exists in women with chronic hypertension in pregnancy and may be important in treatment selection.

Topics: Adult; Angiotensinogen; Biomarkers; Black People; Chronic Disease; Creatinine; Endothelium, Vascular; England; Female; Humans; Hypertension, Pregnancy-Induced; Kidney; Longitudinal Studies; Placenta; Placenta Growth Factor; Pre-Eclampsia; Pregnancy; Prognosis; Randomized Controlled Trials as Topic; Risk Factors; Serum Albumin, Human; Time Factors

Emerging evidence suggests that chronic metabolic acidosis (CMA) may have significant implications in terms of worsening renal disease in CKD patients, but the effect of CMA on renal function and structure has not been fully elucidated.. We studied the acute and chronic consequences of an acid load (AL) on glomerular filtration rate (GFR) and renal histology in C57BL/6 mice. FITC-inulin clearance was performed at several time points; markers of renal fibrosis were studied at mRNA and protein levels; finally, kidney expression of candidate molecules triggering changes in renal function was studied.. Glomerular hyperfiltration occurred within 1-3 days from AL; after 1 week, the GFR returned to baseline and then declined progressively within 15-21 days. The GFR decline was accompanied by the onset of renal fibrosis, as shown by Masson trichrome staining. Markers of renal fibrosis, namely α-smooth muscle actin and collagen-1, increased after 1 day of acid loading in both mRNA and protein levels and remained higher than baseline for up to 21 days. Well-known mediators of renal fibrosis, including transforming growth factor (TGF)-β and the intrarenal renin-angiotensin system (RAS) axis, were increased even before the decline of the GFR.. Acid load caused hyperfiltration acutely and a progressive decline of the GFR chronically; the evidence of renal fibrosis indicates that structural and not only functional renal changes occurred. The concomitant upregulation of TGF-β and intrarenal RAS axis indicates that those factors may be potentially involved in the progression of kidney disease in this setting.

Topics: Acidosis; Actins; Ammonium Chloride; Angiotensinogen; Animals; Chronic Disease; Collagen Type I; Disease Progression; Fibrosis; Gene Expression; Glomerular Filtration Rate; Hydrochloric Acid; Kidney; Male; Mice, Inbred C57BL; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; RNA, Messenger; Transforming Growth Factor beta

The aim of the present study was to determine whether carvedilol-treated chronic heart failure patients have a different prognosis when stratified for a specific combination of a gain-of-function genotype of the adrenergic β-1 receptor gene (ADRB1) (Arg389-homozygous), two gain-of-function genotypes of the angiotensinogen gene (AGT) (Thr174-homozygous and Thr235-homozygous), and a downregulated genotype of the adrenergic β-2 receptor gene (ADRB2) (Gln27-carrier).. Genotyping of 618 patients was carried out using the Sequenoms MassARRAY genotyping system. Outcome was all-cause mortality and statistics were calculated using a multivariable Cox proportional hazards model. Internal validation was performed using the bootstrap procedure.. Eighty-seven of the 618 patients included in the study were treated with carvedilol. There was a significant interaction between the outcome of carvedilol treatment and the combination of the gain-of-function ADRB1 genotype (Arg389-homozygous) and the gain-of-function AGT genotype (Thr174-homozygous) (P(interaction)=0.003; hazard ratio 2.19, 95% confidence interval 1.26-3.78, P=0.005). There was also a significant interaction when the downregulated ADRB2 genotype (Gln27-carrier) was added to the ADRB1/AGT combination (P(interaction)=0.0005; hazard ratio 2.67, 95% confidence interval 1.51-4.72, P=0.0007). Two hundred and four patients were treated with metoprolol. There was no interaction between metoprolol treatment and the specific genotype combinations as there was no difference in the overall survival. The validity of the results was supported by the bootstrap procedure.. We found a doubling of the hazard of mortality in carvedilol-treated patients with the combination of the gain-of-function ADRB1 genotype (Arg389-homozygous), the gain-of-function AGT genotype (Thr174-homozygous), and the downregulated ADRB2 genotype (Gln27-carrier). This might be valuable when stratifying chronic heart failure patients to the right β-blocker therapy.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adult; Aged; Aged, 80 and over; Angiotensinogen; Carbazoles; Carvedilol; Chronic Disease; Female; Genotype; Heart Failure; Humans; Male; Middle Aged; Phenotype; Propanolamines; Proportional Hazards Models; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-2; Retrospective Studies; Survival Analysis

The renoprotective effects of angiotensin receptor blockers vary considerably among individuals. We investigated the renoprotective effects of valsartan according to polymorphisms of the renin-angiotensin system and transforming growth factor-b1 (TGFB1) genes in patients with chronic non-diabetic proteinuric nephropathies.. Two hundred and thirty-nine non-diabetic patients with proteinuria of at least 1 g/day were enrolled. Patients received 80 g of valsartan daily, followed by 160 mg/day after 6 weeks. The follow-up period was 18 months. The status of the angiotensin-converting enzyme (ACE) insertion/deletion, angiotensinogen (AGT) M235T, type 1 angiotensin II receptor (ATR1) A1166C, and TGFB1 C509 and T869C polymorphisms was determined in 162 patients.. Valsartan treatment caused a significant reduction in proteinuria from baseline throughout the study in patients with each genotype of the ACE, AGT and TGFB1 genes. However, patients with the ATR1 AC genotype had no significant reduction in proteinuria from baseline throughout the study course. The median reductions in proteinuria after 6 months were 45.7% and 10.8% in the patients with the ATR1 AA and AC genotypes, respectively (P = 0.034). The annual change in the estimated glomerular filtration rate did not differ significantly among the genotypes for each gene. On multiple regression analysis, the change in proteinuria after 6 months of treatment was independently associated with the ATR1 genotype and the change in blood pressure (P = 0.005 and 0.019, respectively).. Valsartan treatment significantly reduced the blood pressure and urinary protein excretion of patients with chronic non-diabetic proteinuric nephropathies. Interindividual differences in the anti-proteinuric effect of valsartan may be related partly to the ATR1 A1166C polymorphism.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Chronic Disease; Female; Genotype; Humans; Kidney; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Prospective Studies; Protective Agents; Proteinuria; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Tetrazoles; Transforming Growth Factor beta1; Valine; Valsartan

Acute (AMS) and chronic (CMS) mountain sicknesses are illnesses that occur among humans visiting or inhabiting high-altitude environments, respectively. Some individuals are genetically less fit than others when stressed by an extreme high-altitude environment. Seven blood physiological parameters and five genetic polymorphisms were studied in Han patients with AMS and Tibetan patients with CMS.. We compared 98 AMS patients with 60 Han controls as well as 50 CMS patients with 36 Tibetan controls. The genetic loci studied are ACE I/D (rs4340), AGT M235T (rs699), AGTR1 A1166C (rs5186), GNB3 A(-350)G (rs2071057) and APOB A/G (rs693).. All physiological parameters (RBC, HCT, Hb, SaO(2), HR, and BPs/d) studied significantly changed in the CMS patients while SaO(2) and HR changed in the AMS Han patients compared to their controls. The ACE D and AGT 235M alleles were found to be significantly associated with AMS and CMS, respectively, while a significantly high incidence of the G-protein (GNB3) (-350)A allele was found in the AMS patients. ACE (I/D) was significantly associated with HR in CMS patients while the AGT M235T was significantly associated with SaO(2) and BPs/d in AMS patients. APOB A/G was significantly associated with BPs/d in AMS and HR in CMS patients.. AMS and CMS share very similar genetic results for the ACE I/D and AGT M235T polymorphisms indicating that these mutations have an effect on both illnesses.

Topics: Acute Disease; Altitude; Altitude Sickness; Angiotensinogen; China; Chronic Disease; Genome-Wide Association Study; Geography; Hematologic Tests; Humans; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Tibet

Hypertensive patients with large blood pressure variability (BPV) have aggravated end-organ damage. However, the pathogenesis remains unknown. We investigated whether exaggerated BPV aggravates hypertensive cardiac remodeling and function by activating inflammation and angiotensin II-mediated mechanisms. A model of exaggerated BPV superimposed on chronic hypertension was created by performing bilateral sinoaortic denervation (SAD) in spontaneously hypertensive rats (SHRs). SAD increased BPV to a similar extent in Wistar Kyoto rats and SHRs without significant changes in mean blood pressure. SAD aggravated left ventricular and myocyte hypertrophy and myocardial fibrosis to a greater extent and impaired left ventricular systolic function in SHRs. SAD induced monocyte chemoattractant protein-1, transforming growth factor-beta, and angiotensinogen mRNA upregulations and macrophage infiltration of the heart in SHRs. The effects of SAD on cardiac remodeling and inflammation were much smaller in Wistar Kyoto rats compared with SHRs. Circulating levels of norepinephrine, the active form of renin, and inflammatory cytokines were not affected by SAD in Wistar Kyoto rats and SHRs. A subdepressor dose of candesartan abolished the SAD-induced left ventricular/myocyte hypertrophy, myocardial fibrosis, macrophage infiltration, and inductions of monocyte chemoattractant protein-1, transforming growth factor-beta, and angiotensinogen and subsequently prevented systolic dysfunction in SHRs with SAD. These findings suggest that exaggerated BPV induces chronic myocardial inflammation and thereby aggravates cardiac remodeling and systolic function in hypertensive hearts. The cardiac angiotensin II system may play a role in the pathogenesis of cardiac remodeling and dysfunction induced by a combination of hypertension and exaggerated BPV.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Chemokine CCL2; Chronic Disease; Disease Models, Animal; Heart Diseases; Heart Ventricles; Hypertension; Hypertrophy; Inflammation; Macrophages; Male; Myocytes, Cardiac; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetrazoles; Transforming Growth Factor beta; Ventricular Remodeling

Preeclampsia is the major cause of maternal and fetal mortality/morbidity. Because hypertension is an important risk factor for preeclampsia, we investigated whether hypertensive mice that overexpress human renin and angiotensinogen develop superimposed preeclampsia. Given that the mechanisms underlying this disease are still poorly understood, animal models are of great use for elucidation. Blood pressure and proteinuria were measured by telemetry and ELISA, respectively. Heart function was evaluated by echocardiography, whereas pathological cardiac hypertrophy-related genes were assessed by real-time PCR. Soluble fms-like tyrosine kinase 1 plasma concentrations were quantitated by ELISA and placental expression by real-time PCR. Transgenic mice develop de novo proteinuria during gestation and marked blood pressure elevation, which are hallmarks of superimposed preeclampsia on chronic hypertension. Abnormal placentation present in these mothers produced a significant decrease in pup and placental weight and was associated with an increased placental expression of soluble fms-like tyrosine kinase 1. We also found heightened circulating levels of this receptor, when adjusted for placental mass, as has been observed in women who suffer from preeclampsia. Cardiac hypertrophy could be observed in the transgenic mice and was exacerbated by gestation. As a result, heart function was significantly decreased, and markers of pathological hypertrophy were increased. Our data, thus, confirm the characterization of a new model of superimposed preeclampsia on chronic hypertension. Because chronically hypertensive women are at risk of developing the pathology, our model reflects a clinical reality and is, thus, an excellent tool to elucidate the molecular mechanisms triggering this disease.

Topics: Angiotensinogen; Animals; Animals, Newborn; Blood Pressure; Cardiomegaly; Chronic Disease; Disease Models, Animal; Female; Humans; Hypertension; Mice; Mice, Inbred C57BL; Mice, Transgenic; Placenta; Pre-Eclampsia; Pregnancy; Proteinuria; Renin; Renin-Angiotensin System

Despite dramatic improvements in first-year patient and graft survival rates, chronic allograft dysfunction (CAD) remains the leading cause of late renal allograft loss, while current immunologic strategies have little effect on this condition. The renin-angiotensin system (RAS) plays an important role in progression of chronic renal disease. It was shown that plasminogen activator inhibitor-1 (PAI-1) functions in the RAS. This study investigates the possible links between angiotensinogen (AGT M235T), angiotensin-converting enzyme (ACE) and PAI-1 genotypes with CAD. Assessments of polymorphism were performed in 127 renal allograft recipients (77 with CAD and 50 with normal renal function). Fifty healthy subjects were also considered for comparison. Genotypes were determined using polymerase chain reaction (PCR) sequence-specific primers and PCR followed by restriction fragment length polymorphism analysis. Kidney recipients with CAD had significantly higher frequencies of the TT than the recipients without CAD (P < 0.05). The transplant recipients with CAD also had significantly higher frequencies of the DD genotype than those without CAD (P < 0.05). No significant differences were observed between the allelic and genotypic distributions of PAI-1 polymorphisms. Therefore, determination of AGT M235T and ACE genotypes prior to transplantation may be useful to identify patients who are at risk for chronic renal transplant dysfunction.

Topics: Adult; Alleles; Angiotensinogen; Chronic Disease; Demography; Female; Genotype; Graft Rejection; Humans; Linkage Disequilibrium; Male; Peptidyl-Dipeptidase A; Plasminogen Activator Inhibitor 1; Polymorphism, Single Nucleotide; Risk Factors; Tissue Donors; Transplantation, Homologous

Chronic allograft nephropathy (CAN) is a cause of graft loss. The multistage processes that result in CAN are poorly understood. Noninvasive assays for detecting allograft dysfunction and predicting long-term outcomes are a priority in transplantation (Tx).. Renal tissue from kidney transplant patients (KTP) with CAN (n=11) and normal kidneys (NK; n=7) were studied using microarrays. Markers resulting from the microarray analysis (transforming growth factor [TGF]-beta, epidermal growth factor receptor [EGFR], angiotensinogen [AGT]) were tested in urine (Ur) and peripheral blood (PB) samples from the CAN patients (collected at the biopsy time) using reverse-transcriptase real-time polymerase chain reaction. Ur and PB samples from long-term KTP with stable renal function (SRF; n=20) were used as control.. Assuming unequal variances between CAN and NK, using a false discovery rate of 0.005, and running 1,000 of all possible permutations, 728 probe sets were differentially expressed. Genes related to fibrosis and extracellular matrix deposition (i.e., TGF-beta, laminin, gamma 2, metalloproteinases-9, and collagen type IX alpha 3) were up-regulated. Genes related to immunoglobulins, B cells, T-cell receptor, nuclear factor of activated T cells, and cytokine and chemokines receptors were also upregulated. EGFR and growth factor receptor activity (FGFR)2 were downregulated in CAN samples. AGT, EGFR, and TGF-beta levels were statistical different in urine but not in blood samples of CAN patients when compared to KTP with SRF (P<0.001, P=0.04, and P<0.001, respectively).. Genes related to fibrosis, extracellular matrix deposition, and immune response were found up-regulated in CAN. Markers resulting from the microarray analysis were differentially expressed in Ur samples of the CAN patients and in concordance with the microarray profiles.

Topics: Adult; Angiotensinogen; Biomarkers; Chronic Disease; ErbB Receptors; Female; Gene Expression Profiling; Gene Expression Regulation; Graft Rejection; Humans; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta; Transplantation, Homologous

The renin-angiotensin system (RAS) regulates BP and may affect chronic kidney disease (CKD) through induction of tissue growth and fibrosis. The angiotensinogen (AGT) promoter G(-6) allele lowers transcription and is inversely associated with hypertension. In white individuals, the A1166C 3'-UTR variant of angiotensin II type 1 receptor (AT1R) has been associated with CKD. CKD associations with these RAS genes are uncertain in high-risk black populations. A prospective population-based study of CKD risk was conducted among 3706 black individuals without severe renal dysfunction at baseline (serum creatinine > or =177 micromol/L [2.0 mg/dl] for men, > or =159 micromol/L [1.8 mg/dl] for women) to examine associations with AGT and AT1R. Incident CKD progression was defined as kidney disease hospitalization or increase in serum creatinine level > or =35 micromol/L (0.4 mg/dl) above baseline. During mean follow-up of 10.2 yr, CKD progression incidence rate (per 1000 person-years) was 8.2 (n = 312 cases). Risk was lower for AGT G(-6) carriers compared with A(-6) (incidence 6.9 versus 9.0; log-rank P = 0.03) and nonsignificantly higher among AT1R C1166 carriers. Adjusting for hypertension and major CKD risk factors, AGT G(-6)decreased risk (relative risk 0.75; 95% confidence interval 0.57 to 0.98). AT1R C1166 increased risk only among those with hypertension (relative risk 1.65; 95% confidence interval 1.14 to 2.39). The AGT G(-6)A polymorphism may play a role in CKD progression in black individuals, consistent with in vitro effects on AGT levels and renal remodeling but independent of BP. The AT1R C1166 allele may increase susceptibility but only in the presence of hypertension.

Topics: Angiotensinogen; Atherosclerosis; Black or African American; Chronic Disease; Female; Genetic Variation; Genotype; Humans; Kidney Diseases; Male; Middle Aged; Prospective Studies; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Assessment

Renin-angiotensin System is essential for the homeostasis of blood pressure in humans. The roles of renin-angiotensin system gene polymorphisms including angiotensinogen, angiotensin-converting enzyme, renin and angiotensin II receptor, type 1 genes in the pathogenesis of preeclampsia have been extensively studied, but most association studies produced either negative or inconsistent results. Prolylcarboxypeptidase encodes a lysosomal enzyme and is a regulator for both renin-angiotensin system and the kallikrein-kinin system. There is no published study on prolylcarboxypeptidase gene and preeclampsia.. We investigated the independent and joint association of five polymorphisms in angiotensinogen, angiotensin-converting enzyme, and prolylcarboxypeptidase gene and chronic hypertension with the risk of preeclampsia in 125 preeclamptic and 1040 non-preeclamptic black women enrolled at the Boston Medical Center. We used logistic regression models to estimate the odds ratios of risk for preeclampsia associated with each gene polymorphism and its joint association with chronic hypertension.. No association was found in four polymorphisms in angiotensinogen and angiotensin-converting enzyme. Prolylcarboxypeptidase E112D (rs2298668) D allele along and jointly with chronic hypertension were associated with a significantly increased risk of preeclampsia. Compared to women with homozygous EE genotype and without chronic hypertension, higher risks of preeclampsia were observed in DD women without chronic hypertension (OR = 3.7, 95% CI, 1.2 - 12.4) and EE women with chronic hypertension (OR = 9.1, 95% CI: 4.7 - 17.6). Women with both D allele and chronic hypertension had the highest risk (OR = 158, 95% CI, 25-infinite). This finding was validated in an independent sample of 1,015 non-black women. We further compared the prolylcarboxypeptidase transcript levels in peripheral blood cells of 23 preeclamptic (30% with chronic hypertension) and 51 non-preeclamptic (6% with chronic hypertension) women 2 - 3 days after delivery. The PRCP transcript levels were lower in ED/DD women than in EE woman (P = .03) and lower in preeclamptic women than in non-preeclamptic women (P = .007).. Our data showed that prolylcarboxypeptidase D allele coupled with chronic hypertension was associated with a significantly increased risk of preeclampsia in both black and non-black women. Gene expression assays lent further support for the functional significance of prolylcarboxypeptidase in the etiology of preeclampsia.

Topics: Adult; Angiotensinogen; Black or African American; Boston; Carboxypeptidases; Case-Control Studies; Chronic Disease; Female; Gene Expression; Genotype; Humans; Hypertension; Odds Ratio; Peptidyl-Dipeptidase A; Phenotype; Polymorphism, Single Nucleotide; Pre-Eclampsia; Pregnancy; Renin-Angiotensin System; White People

The role of interaction of polymorphisms in the Renin-Angiotensin-System (RAS) with angiotensin converting enzyme (ACE) or angiotensin receptor (AGTR1) inhibitors (RAS inhibitors) is unknown, as is the role of such therapy in end stage renal disease (ESRD) patients.. We enrolled all 445 prevalent patients with diabetic nephropathy receiving maintenance hemodialysis in 30 centers in Southern Germany from August 1999 to January 2000 for prospective survival analysis until December 2003. Blood pressure and medication was recorded at inclusion. We determined survival specific for allelic variants of the ACE (insertion/deletion), Angiotensinogen (M235T) and AGTR1 (A1166C) genes. The effect of therapy with RAS inhibitors at study inclusion was determined for the allelic variants of each gene. The primary end point was all cause mortality (ACM).. For all polymorphisms, and for therapy with RAS inhibitors there was no significant effect on survival in the complete collective (n = 445), though there was an insignificant trend for improved survival in patients on AGTR1 antagonists. Increased ACM risk was associated with treatment with RAS inhibitors only in patients homozygous for the wild type AGTR1 1166A allele (HR 1.65, p = 0.01). For all other polymorphisms, therapy with RAS inhibitors had no significant effect on ACM, irrespective of genotype. Similar results were obtained in patients with systolic ventricular dysfunction.. Our data do not show a survival advantage for type 2 diabetes hemodialysis patients receiving RAS inhibiting therapy. In addition, our data indicate that allelic variation in RAS genes and pharmacogenetic interaction with RAS inhibition does not affect mortality risk in diabetic hemodialysis patients.

Topics: Aged; Alleles; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Blood Pressure; Chronic Disease; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Genetic Variation; Genotype; Humans; Male; Peptidyl-Dipeptidase A; Prospective Studies; Receptor, Angiotensin, Type 1; Renal Dialysis; Renin-Angiotensin System; Survival Rate; Treatment Outcome

Genetic differences between Asians and Caucasians may be involved in the rapid increase in lifestyle-related diseases in the Asia-Pacific region that has coincided with Westernisation of diets in the region. In the present study, we assessed correlation between 10 single nucleotide polymorphisms (SNPs) and chronic disease risk factors in age-matched and population-based groups in four Asian-Pacific locations: Okinawa, Palau and Thailand (two areas). The following allelic SNP profiles significantly differed (p<0.01) among the four populations, in both men and women: uncoupling protein 2 (UCP2), uncoupling protein 3 promoter (UCP3p), leptin receptor (LEPR) exon 6, and angiotensinogen (AGTa-20c). Multiple regression analyses showed significant associations between SNPs and clinical data. For men, these associations were between beta3 adrenergic receptor (beta3AR) and diastolic blood pressure (DBP) (p<0.01), UCP3p and total cholesterol (p<0.01), UCP2 and age (p<0.05), and AGTa-20c and age (p<0.01). For women, these associations were between LEPR exon 14 and body mass index (BMI) (p<0.05), UCP2 and systolic blood pressure (p<0.05), UCP3p and DBP (p<0.05), UCP2 and DBP (p<0.01), apolipoprotein E (ApoE)nd total cholesterol (p<0.01), beta3AR and triglyceride (p<0.05), AGTa-20c and triglyceride (p<0.05), and UCP2 and age (p<0.05). These results illustrate the interrelationships among SNPs and risk factors in the Asia-Pacific including China and Japan.

Topics: Aged; Angiotensinogen; Apolipoproteins E; Asia; Asian People; Blood Pressure; Body Mass Index; Chronic Disease; Female; Gene Expression; Humans; Ion Channels; Life Style; Lipids; Male; Middle Aged; Mitochondrial Proteins; Pacific Islands; Peroxisome Proliferator-Activated Receptors; Polymorphism, Single Nucleotide; Receptors, Adrenergic, beta-3; Receptors, Leptin; Uncoupling Protein 2; Uncoupling Protein 3; White People

We examined the hypothesis that the renin-angiotensin system plays an important role in vascular remodeling (defined as reduced external diameter) during chronic hypertension. We measured pressure, diameter, and cross-sectional area of the vessel wall in maximally dilated cerebral arterioles in transgenic mice that overexpress both human renin and human angiotensinogen and in spontaneously hypertensive mice, a model of chronic hypertension that is thought to develop independently of the renin-angiotensin system. Systemic arterial pressure under conscious conditions was increased by similar amounts in transgenically hypertensive mice (153+/-6 versus 117+/-4 mm Hg in controls; mean+/-SE, P<0.05) and spontaneously hypertensive mice (148+/-5 versus 112+/-5 mm Hg; P<0.05). The external diameter of maximally dilated cerebral arterioles was reduced in transgenically hypertensive mice (52+/-2 versus 66+/-3 micro m; P<0.05), but not in spontaneously hypertensive mice (58+/-4 versus 60+/-4 micro m; P>0.05). The cross-sectional area of the vessel wall was increased in both transgenically hypertensive mice (504+/-53 versus 379+/-37 microm2; P<0.05) and spontaneously hypertensive mice (488+/-40 versus 328+/-38 microm2; P<0.05). During maximal dilatation, the stress-strain curves in cerebral arterioles of transgenically hypertensive mice and spontaneously hypertensive mice were shifted to the right of the curves in corresponding controls, an indication that arteriolar distensibility was increased in the transgenically and spontaneously hypertensive groups. Thus, cerebral arterioles undergo remodeling and hypertrophy in transgenically hypertensive mice, but only hypertrophy in spontaneously hypertensive mice. These findings support the hypothesis that the renin-angiotensin system is an important determinant of vascular remodeling during chronic hypertension.

Topics: Angiotensinogen; Animals; Arterioles; Blood Pressure; Chronic Disease; Humans; Hypertension; Hypertrophy; Mice; Mice, Transgenic; Renin; Renin-Angiotensin System; Telencephalon; Vasodilation

The aim of the study was to focus on the relationship between the angiotensinogen (AGT) gene polymorphisms, M235T and promoter G(-6)A, and chronic heart failure in the Czech population. A total of 158 patients with chronic heart failure (functional class NYHA II-IV, ejection fraction <40%, cardiothoracic index >50%) were compared with a control group of 200 subjects of similar age and sex distribution, without any personal history of cardiovascular diseases. The AGT gene polymorphisms were detected by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. No significant differences in distributions of AGT genotypes between patients with chronic heart failure (CHF) and controls were found. The differences in distributions of alleles in AGT M235T (P(a)=0.02) and genotypes in AGT G(-6)A (P(g)=0.017) were found within women groups. Within CHF patients the distribution of AGT G(-6)A genotypes was not consistent with Hardy-Weinberg equilibrium (P=0.0001). We found significant relative risk of CHF in the GGMT genotype, OR=2.63 with 95% CI 1.39-4.95, P(corr)=0.01 (in the male group OR=1.83, 95% CI 0.92-3.66, P(corr)=0.3; in the female group OR=15.5, 95% CI 1.86-129.42, P(corr)=0.008). We provide evidence of increased risk in subjects with the GGMT variant of associated genotype of AGT gene for CHF, especially of fifteen-fold risk of this variant in women.

Topics: Adult; Aged; Aged, 80 and over; Angiotensinogen; Case-Control Studies; Chronic Disease; Czech Republic; Female; Heart Failure; Humans; Male; Middle Aged; Polymorphism, Genetic; Sex Factors

Evidence exists for the presence of a functional angiotensin system in the carotid body, which can modulate the excitability of the carotid body chemoreceptors. In the present study, the effect of chronic hypoxia on the expression and localization of the angiotensinogen (AGT) and angiotensin-converting enzyme (ACE), the two critical components of an intrinsic angiotensin-generating system in the rat carotid body, are investigated by in situ hybridization histochemistry, semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. In situ hybridization showed that the messenger RNA (mRNA) expression of AGT was localized within the type-I glomus cells of the carotid body, which was subjected to be upregulated under the stress of chronic hypoxia. RT-PCR further confirmed a significant increase in the expression of AGT mRNA by chronic hypoxia. Consistently, Western blot analysis demonstrated that chronic hypoxia could elicit the upregulation of AGT protein in chronically hypoxic carotid bodies when compared with their normoxic controls. On the other hand, there was a slight but significant increase in ACE mRNA expression during chronic hypoxia. This study suggests that chronic hypoxia can activate a local angiotensin-generating system in the carotid body, notably its obligatory component AGT. The activation of such an intrinsic, angiotensin-generating system in the carotid body during chronic hypoxia should be important in the modulation of cardiopulmonary adaptation in the hypoxic ventilatory response and the electrolyte as well as water homeostasis.

Topics: Adaptation, Physiological; Angiotensinogen; Angiotensins; Animals; Carotid Body; Chemoreceptor Cells; Chronic Disease; Hypoxia; Male; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; RNA, Messenger; Up-Regulation

Transforming growth factor (TGF)-beta1 is important in fibrogenesis and has been involved in the pathogenesis of chronic allograft nephropathy (CAN). The angiotensinogen (AGT) gene encodes the only glycoprotein known to be a precursor of the vasopressor angiotensin II. Angiotensin II is also a growth factor and a profibrogenic cytokine. It mediates the induction of TGF-beta1. We studied the relationship among the intragraft expression of AGT, TGF-beta1, and CAN in stable renal transplant patients (RTP). We used a competitive quantitative reverse transcriptase-polymerase chain reaction (RT-PCR)-ELISA assay to identify intragraft amounts of AGT expression in RTP and correlated it with TGF-beta1 mRNA expression. We studied and performed kidney biopsies on 12 RTP with long-functioning grafts and 6 RTP in the immediate posttransplantation period (7 days) who had acute tubular necrosis as control. Histology was based on Banff working classification criteria. Total RNA was isolated from biopsy specimens. For RT-PCR-ELISA, we created heterologous RNA competitors that coamplified with the same primers as AGT and TGF-beta1. Six of 12 long RTP had proteinuria >1000 mg/24 hr and 6 had proteinuria <1000 mg/24 hr. The differences between Banff grades (P =0.03), AGT, and TGF-beta1 levels by RT-PCR-ELISA were statistically significant between both groups (106.2+/-60.7 vs. 34.1+/-11.9 pg/microg total RNA [P =0.01] and 5954+/-5612 vs. 436+/-517 transcripts/microg total RNA [P =0.01], respectively). The control group showed AGT levels of 25+/-12.2 pg/microg total RNA and TGF-beta1 levels of 228+/-111 transcripts/microg total RNA, significant only for the higher proteinuria group (P=0.01 and P=0.04, respectively). There was a correlation between AGT and TGF-beta1 in both groups (r=0.96, P=0.001). We showed a relationship between mRNA expression of AGT and TGF-beta1 in kidney transplant patients with different grades of CAN and proteinuria.

Topics: Adult; Angiotensinogen; Cadaver; Chronic Disease; Cyclosporine; Female; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; RNA, Messenger; Tissue Donors; Transcription, Genetic; Transforming Growth Factor beta; Transplantation, Homologous

The circulating renin-angiotensin system (RAS) plays a crucial role in the regulation of blood pressure, electrolytes, and fluid homeostasis. In contrast to the circulating RAS, the presence of an intrinsic RAS has been demonstrated in different tissues/organs, which may affect both local and global functions of a biologic system. Our previous studies provided solid evidence of the existence of a local RAS in rat pancreas. Our further investigation showed that such a pancreatic RAS could be activated by experimental models of chronic hypoxia and chemically induced pancreatitis. These previous findings formed the basis for the current study.. Adult Sprague-Dawley rats were exposed to isobaric hypoxia (10% O2), and the effects on the circulating and pancreatic RAS were documented.. The current study shows that exposure of rats to isobaric hypoxia caused a time-dependent increase in plasma renin activity. The activation of circulating RAS by hypoxia was associated with a parallel upregulation of local RAS components, including the mRNA expression of angiotensinogen and angiotensin II receptor types I and II in the pancreas.. The upregulation of local pancreatic RAS, along with its counterpart circulating RAS, may be responsible for both physiologic and pathophysiologic aspects of a biologic system under chronic hypoxic stress.

Topics: Angiotensinogen; Animals; Chronic Disease; Hypoxia; Kinetics; Pancreas; Rats; Rats, Sprague-Dawley; Receptors, Angiotensin; Renin; Renin-Angiotensin System; RNA, Messenger; Up-Regulation

The presence of an intrinsic renin-angiotensin system (RAS) in the rat epididymis has been previously established by showing the expression of several key RAS components, and in particular angiotensinogen, the indispensable element for the intracellular generation of angiotensin II. In this study, the possible involvement of this local epididymal RAS in the testicular effects of chronic hypoxia was investigated. Semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR), Western blotting and by in situ hybridization histochemistry of the rat epididymis were used to show changes in localization and expression of angiotensinogen. Results from RT-PCR analysis demonstrated that chronic hypoxia caused a marked decrease (60%) in the expression of angiotensinogen mRNA, when compared with that in the normoxic epididymis. Western blot analysis demonstrated a less decrease (35%) in the expression of angiotensinogen protein. In situ hybridization histochemistry showed that the reduced angiotensinogen mRNA in chronic hypoxia was specifically localized to the epididymal epithelium from the cauda, corpus and caput regions of the epididymis; a distribution similar to that of normoxic rats. It was concluded that chronic hypoxia decreases the transcriptional and translational expression of angiotensinogen, and thus local formation of angiotensin II, in the rat epididymis.

Topics: Angiotensin II; Angiotensinogen; Animals; Blotting, Western; Chronic Disease; Down-Regulation; Epididymis; Hypoxia; In Situ Hybridization; Male; Oligonucleotides, Antisense; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

The systemic renin-angiotensin system (RAS) plays an important role in blood pressure (BP) regulation during the development of 2-kidney, 1 clip (2K1C) hypertension. Its contributions decrease with time after constriction of the renal artery. During the chronic phase, the peripheral RAS returns to normal, but the hypertension is sustained for months. We hypothesized that in this phase the brain RAS contributes to the maintenance of high BP. To test the hypothesis, we studied the role of brain RAS by decreasing the synthesis of angiotensinogen (AGT) and the angiotensin II (Ang II) type 1a receptor (AT(1)R) with intracerebroventricular injections of antisense oligonucleotides (AS-ODNs). The response of systolic BP (SBP) to AS-ODNs to AGT mRNA was studied in 2K1C rats at 6 months after clipping, and the response to AS-ODNs to AT(1)R mRNA was studied at 10 months after clipping. Intracerebroventricular injection of AS-ODN-AGT (200 microgram/kg, n=5) significantly decreased SBP (-22+/-6 mm Hg, P<0.05) compared with the sense ODN (n=5) and saline (n=3) groups. Intracerebroventricular injection of AS-ODN-AGT reduced the elevated hypothalamic Ang II level. The hypothalamic Ang II content in sense ODN and saline groups was significantly (P<0.05) higher than in the nonclipped group. Compared with inverted ODN, intracerebroventricular injection of AS-ODN-AT(1)R (250 microgram/kg, n=6) significantly decreased SBP (-26+/-8 mm Hg, P<0.05) for 3 days after injection. This was a brain effect because intravenous AS-ODN-AT(1)R at a dose of 250 to 500 microgram/kg did not affect SBP. These results suggest that the brain RAS plays an important role in maintaining the elevated SBP in chronic 2K1C hypertension.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensinogen; Animals; Blood Pressure; Brain; Chronic Disease; Hypertension; Hypertension, Renovascular; Hypothalamus; Injections, Intraventricular; Male; Oligonucleotides, Antisense; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System; RNA, Messenger; Time Factors

Previous studies have provided evidence that several key elements of renin-angiotensin system (RAS) are present in the rat pancreas, notably angiotensinogen, which is mandatory for intracellular generation of physiologically active angiotensin II. The data support the existence of an intrinsic RAS, which may be important for pancreatic blood flow and ductal anion secretion. In the present study, the effect of chronic hypoxia on the expression of RAS components, particularly at the levels of its precursor angiotensinogen and its receptor subtypes AT(1) and AT(2), were investigated in the rat pancreas. Results from western blot and semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR) analyses unequivocally showed that chronic hypoxia caused a marked increase in angiotensinogen both at the protein and gene levels when compared with that in the normoxic pancreas. However, results from RT-PCR showed that there was a differential effect of chronic hypoxia on the expression of AT(1) and AT(2) receptor subtypes, which exhibited subtype-specific changes in gene expression. For AT(1), chronic hypoxia did not cause a significant change in mRNA expression for AT(1a) but a significant increase in mRNA expression for AT(1b). For AT(2), chronic hypoxia caused a marked increase in its mRNA expression. The increased expression of RAS component genes by chronic hypoxia and its significance of changes may be important for physiological and pathophysiological aspects of the pancreas.

Topics: Angiotensinogen; Animals; Animals, Newborn; Chronic Disease; Hypoxia; Pancreas; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Recent association and linkage studies suggested that angiotensinogen may play an important role in the pathogenasis of essential hypertension. However, there is little information in human concerning a relationship between plasma angiotensinogen levels and the angiotensinogen mRNA expression in the liver, which is the main production site of angiotensinogen. Therefore, the aim of this study was to examine whether hepatic angiotensinogen gene expression determines the level of circulating angiotensinogen and the activity of the renin-angiotensin system in humans. The subjects were 36 patients with chronic hepatitis. Blood was collected from each patients for estimation of plasma renin activity, plasma angiotensinogen and angiotensin II concentrations and several parameters of liver function. In addition, total RNA was isolated from liver biopsy specimens, which were then used to measure angiotensinogen mRNA with Northern blot analysis. Levels of angiotensinogen mRNA were detected easily in the liver biopsy specimens in all of the patients. Hepatic angiotensinogen mRNA levels were positively correlated with plasma angiotensinogen levels (r=0.41, P=0.013). In contrast, hepatic angiotensinogen mRNA levels did not show any significant relationship with plasma renin activity, plasma angiotensin II concentration, histological subgroup of hepatitis, histological activity index and parameters of liver function tests. The present study demonstrated, for the first time, that hepatic angiotensinogen mRNA levels correlated with plasma angiotensinogen concentration in humans.

Topics: Adult; Aged; Angiotensinogen; Chronic Disease; Female; Hepatitis; Humans; Liver; Male; Middle Aged; Renin-Angiotensin System; RNA, Messenger; Serum Albumin

The intrarenal renin-angiotensin system (RAS) may contribute to the pathophysiology of heart failure by the generation of angiotensin II at local sites within the kidneys. Angiotensin II may directly influence renal hemodynamics, glomerular contractility, and tubular sodium reabsorption, thereby promoting sodium and fluid retention in this syndrome. In the present study, we examined components of the circulating RAS as well as the intrarenal expressions of renin and angiotensinogen mRNA in rats with stable compensated heart failure (HF) 12 wk after experimental myocardial infarction. Renal angiotensinogen mRNA level in vehicle-treated HF rats increased 47%, as compared with sham control rats (P = 0.001). The increase in angiotensinogen mRNA levels was more pronounced in animals with medium (46%, P < 0.05) and large (66%, P < 0.05) infarcts than in those with small infarcts (31%, P = NS). There were no differences in liver angiotensinogen mRNA, circulating angiotensinogen, angiotensin II, plasma renin concentration (PRC), kidney renin content (KRC), and renal renin mRNA level between sham and HFv. In addition, in a separate group of rats with heart failure, we demonstrated that renal angiotensin II concentration increased twofold (P < 0.05) as compared with that of age-matched sham operated controls. A parallel group of heart failure rats (HFe, n = 11) was treated with enalapril (25 mg/kg per d) in drinking water for 6 wk before these measurements. Blood pressure decreased significantly during treatment (91 vs. 103 mm Hg, P < 0.05). Enalapril treatment in HF rats increased renin mRNA level (2.5-fold, P < 0.005), KRC (5.6-fold, P = 0.005), and PRC (15.5-fold, P < 0.005). The increase in renal angiotensinogen mRNA level observed in HFv rats was markedly attenuated in enalapril treated HF rats (P < 0.001), suggesting a positive feedback of angiotensin II on renal angiotensinogen synthesis. These findings demonstrate an activation of intrarenal RAS, but no changes in the circulating counterpart in this model of experimental heart failure, and they support the concept that the intrinsic renal RAS may contribute to the pathophysiology in this syndrome.

Topics: Angiotensinogen; Animals; Chronic Disease; Enalapril; Heart Failure; Kidney; Male; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; RNA, Messenger

The renin substrate angiotensinogen (AGT) belongs to a supergene family of proteins that also includes alpha 1-antitrypsin (AAT) and alpha 1-antichymotrypsin (ACT), acute-phase reactants with known serine proteinase inhibitory (serpin) function. AGT lacks a known inhibitory function but is an acute-phase reactant. In this study we have compared the plasma levels, as analysed by electroimmunoassay, of AGT with AAT in patients with different types of chronic liver disease. AAT levels are regularly elevated in liver disease patients in contrast to AGT, which remains normal until late in the disease course. The AGT levels (mean +/- SD) were: in alcoholic cirrhosis (n = 19) 100 +/- 27.3%, in chronic active hepatitis (n = 14) 100 +/- 23.2%, in primary biliary cirrhosis (n = 18) 106 +/- 26.1% and in non-alcoholic cirrhosis (n = 15) 92 +/- 38.4%. Only occasionally were levels less than 50% of normal seen. In general, AGT levels were unrelated to sex and type of underlying liver disease and did not correlate with degree of hepatocellular impairment. Crossed immunoelectrophoresis showed no abnormal charge heterogeneity of AGT in patients with low levels. Our data are consistent with a dissociate expression of the homologous serpin genes in chronic liver disease. We speculate that the magnitude of the dissociated response is influenced by hormonal factors.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; alpha 1-Antitrypsin; Angiotensinogen; Arthritis, Rheumatoid; Chronic Disease; Cross-Sectional Studies; Female; Humans; Immunochemistry; Immunoelectrophoresis, Two-Dimensional; Infant, Newborn; Liver Diseases; Longitudinal Studies; Male; Middle Aged

The plasma level of angiotensinogen during the chronic phase of inflammation was studied for comparison with those of other acute-phase reactants in rat adjuvant arthritis. In response to a single injection of Freund's complete adjuvant, this level exhibited a transient increase during the first 24 h. By contrast, increased levels of plasma T-kininogen and alpha 2-macroglobulin, typical acute-phase reactions in the rat, were maintained during the 4-week experimental period. These results suggest that the hepatic synthesis of angiotensinogen is stimulated only in the early phase of chronic inflammation, and therefore that the mechanism underlying the acute-phase response of angiotensinogen is distinct from those currently suggested for other acute-phase reactants.

Topics: Acute-Phase Reaction; alpha-Macroglobulins; Angiotensinogen; Animals; Arthritis; Arthritis, Experimental; Chronic Disease; Corticosterone; Inflammation; Kininogens; Male; Rats